Head fake

How Prozac sent the science of depression in the wrong direction

PROZAC IS ONE of the most successful drugs of all time. Since its introduction as an antidepressant more than 20 years ago, Prozac has been prescribed to more than 54 million people around the world, and prevented untold amounts of suffering.

But the success of Prozac hasn't simply transformed the treatment of depression: it has also transformed the science of depression. For decades, researchers struggled to identify the underlying cause of depression, and patients were forced to endure a series of ineffective treatments. But then came Prozac. Like many other antidepressants, Prozac increases the brain's supply of serotonin, a neurotransmitter. The drug's effectiveness inspired an elegant theory, known as the chemical hypothesis: Sadness is simply a lack of chemical happiness. The little blue pills cheer us up because they give the brain what it has been missing.

There's only one problem with this theory of depression: it's almost certainly wrong, or at the very least woefully incomplete. Experiments have since shown that lowering people's serotonin levels does not make them depressed, nor does it worsen their symptoms if they are already depressed.

In recent years, scientists have developed a novel theory of what falters in the depressed brain. Instead of seeing the disease as the result of a chemical imbalance, these researchers argue that the brain's cells are shrinking and dying. This theory has gained momentum in the past few months, with the publication of several high profile scientific papers. The effectiveness of Prozac, these scientists say, has little to do with the amount of serotonin in the brain. Rather, the drug works because it helps heal our neurons, allowing them to grow and thrive again.

In this sense, Prozac is simply a bottled version of other activities that have a similar effect, such as physical exercise. They aren't happy pills, but healing pills.

These discoveries are causing scientists to fundamentally reimagine depression. While the mental illness is often defined in terms of its emotional symptoms - this led a generation of researchers to search for the chemicals, like serotonin, that might trigger such distorted moods - researchers are now focusing on more systematic changes in the depressed brain.

"The best way to think about depression is as a mild neurodegenerative disorder," says Ronald Duman, a professor of psychiatry and pharmacology at Yale. "Your brain cells atrophy, just like in other diseases [such as Alzheimer's and Parkinson's]. The only difference with depression is that it's reversible. The brain can recover."

Given the prevalence of depression - more than 16 percent of people will suffer from a major depressive episode at some point in their lives - a more accurate scientific understanding of the disease is of immense value. In fact, this research is already being used to develop more effective treatments for the mental illness, some of which are currently in clinical trials.

The progress exemplifies an important feature of modern medicine, which is the transition from a symptom-based understanding of a disease - depression is an illness of unrelenting sadness - to a more detailed biological understanding, in which the disease is categorized and treated based on its specific anatomical underpinnings.

In the 19th century, the "fever" was a common medical illness. Of course, doctors now realize that a fever is merely a common symptom of many different diseases, from the flu to leukemia.

Likewise, when Richard Nixon declared a "War on Cancer" in 1971, scientists largely defined cancer in terms of its most tangible characteristic: uncontrolled growth leading to a tumor. As a result, every cancer was treated with the same blunt tools. Over time, of course, scientists have discovered that cancer is not a single disease with a single biological cause. Breast cancer, for instance, can be triggered by a wide variety of genes and environmental risk factors. Because doctors can look beyond the superficial similarities of the symptoms - all tumors are not created equal - they are able to tailor their treatments to the specific disease.

Neuroscience is only beginning to catch up. Thanks to a variety of new experimental tools, such as brain scanners and DNA microarrays, researchers are now refining their understanding of mental illness. In many instances, this means recategorizing disorders, so that patients are no longer diagnosed solely in terms of their most obvious symptoms.

"We used to think there was only one kind of anemia," says Arturas Petronis, a scientist at the University of Toronto who investigates the underlying causes of schizophrenia. "But now we know there are at least 15 different kinds. We'll likely learn the same thing about many mental illnesses."

. . .

One of the first cracks in the chemical hypothesis of depression came from a phenomenon known as the "Prozac lag." Antidepressants increase the amount of serotonin in the brain within hours, but the beneficial effects are not usually felt for weeks.

This led neuroscientists to wonder if something besides serotonin might be responsible. Duman, for instance, began to study a class of proteins known as trophic factors, which help neurons grow and survive. Trophe is Greek for nourishment; what sunlight and water do for trees, trophic factors do for brain cells. Numerous studies had shown that chronic stress damages the brain by suppressing the release of trophic factors. In a series of influential papers published earlier this decade, Duman demonstrated that the same destructive hallmark is seen in depression, so that our neurons are deprived of what they need.

"The mental illness occurs when these stress mechanisms in the brain spiral out of control," he says.

Once that happens, the brain begins to shut itself down, suppressing all but the most essential upkeep. Not only do neurons stop growing, but the brain seems to stop creating new cells. A 2003 study, led by Columbia University neuroscientist Rene Hen, found that when the birth of new brain cells was blocked with low doses of radiation in "depressed" rats, antidepressants stopped working.

A recent study by Italian researchers, published in the journal Science, helps to reveal another mechanism by which antidepressants reverse the damage of depression. The scientists were interested in seeing if fluoxetine, the active ingredient of Prozac, could increase the potential of brain cells in the adult rat. They studied animals with severe cases of "lazy eye," a condition characterized by poor vision in one eye due to underdevelopment of the visual cortex. The scientists showed that fluoxetine gave brain cells the ability to take on new roles and form new connections, which erased the symptoms of the disorder.

"The drug appears to make brain cells quite young," says Jose Vettencourt, a lead author. The scientists are currently repeating the experiment with humans, raising the possibility that fluoxetine will soon be used to treat lazy eye and related conditions.

"Even five years ago, this would have seemed like a very strange idea," Vettencourt says.

Duman's lab has demonstrated, in a paper published earlier this year, that physical exercise seems to stimulate the same regenerative pathways. Mice given access to running wheels not only showed reduced anxiety and stress, but also increased levels of the same trophic factors activated by antidepressants. When the activity of these trophic factors was blocked, the benefits of exercise disappeared. The mice stayed stressed, even when they were allowed to run on their wheel.

It is jarring to think of depression in terms of atrophied brain cells, rather than an altered emotional state. It is called "depression," after all. Yet these scientists argue that the name conceals the fundamental nature of the illness, in which the building blocks of the brain - neurons - start to crumble. This leads, over time, to the shrinking of certain brain structures, like the hippocampus, which the brain needs to function normally.

In fact, many scientists are now paying increased attention to the frequently neglected symptoms of people suffering from depression, which include problems with learning and memory and sensory deficits for smell and taste. Other researchers are studying the ways in which depression interferes with basic bodily processes, such as sleeping, sex drive, and weight control. Like the paralyzing sadness, which remains the most obvious manifestation of the mental illness, these symptoms are also byproducts of a brain that's literally withering away.

"Depression is caused by problems with the most fundamental thing the brain does, which is process information," says Eero Castren, a neuroscientist at the University of Helsinki. "It's much more than just an inability to experience pleasure."

This new scientific understanding of depression also offers a new way to think about the role of drugs in recovery. While antidepressants help brain cells recover their vigor and form new connections, Castren says that patients must still work to cement these connections in place, perhaps with therapy. He compares antidepressants with anabolic steroids, which increase muscle mass only when subjects also go to the gym.

"If you just sit on your couch, then steroids aren't going to be very effective," he says. "Antidepressants are the same way: if you want the drug to work for you, then you have to work for the drug."

Jonah Lehrer is an editor at large at Seed magazine and the author of "Proust Was a Neuroscientist." He is a regular contributor to Ideas.